Booster and boosted in the same pill: pharmacological considerations

Transcription

1 Booster and boosted in the same pill: pharmacological considerations Stefano Bonora University of Torino

2 2000/2017 ARVs that still need boosting ARV LPV ATV DRV EVG Available as Kaletra (LPV/r) 1 (200/50 BID Tn&Tex) Reyataz (ATV*), 2 Evotaz (ATV/COBI) 3 (300/150 QD Tn&Tex) Prezista (DRV*), 4 Prezcobix or Rezolsta (DRV/COBI) 5 (800/150 QD Tn&Tex no res) DRV/C/F/TAF (800/150/200/10 QD) 8 Vitekta (EVG), 6 Stribild (EVG/COBI/TDF/FTC) 7 (150/150/200/245 QD Tn&Tex no res) Genvoya E/C/F/TAF (150/150/200/10 QD) 8 *Requires co-administration with a booster Approved in 2015 by the FDA Requires co-administration with a boosted PI* 1. Kaletra summary of product characteristics; 2. Reyataz summary of product characteristics; 3. Evotaz US prescribing information; 4. Prezista summary of product characteristics; 5. Rezolsta summary of product characteristics; 6. Vitekta summary of product characteristics; 7. Stribild summary of product characteristics 8-Clinical Trials gov accessed 11/11/2015

3 Importance of metabolism and transport in relation to systemic drug levels 2) hepatocytes UGTs drug 100% CYP3A4 2 OATP1B1 OATP1B3 OCT1 1) enterocytes OATP1A2 OATP2B1 1 P-gp BCRP MRP2 CYP3A4 Adapted from Bailey DG et al. CMAJ 2013

4 Limits of ritonavir as a booster PK Issues - Not selective as CYP3A4 inhibitor - CYP2D6 inhibitor - CYP2C9, CYP2C19, CYP1A2, UGT inducer - Inhibitor of membrane transporters

5 Cobicistat is structurally similar to ritonavir..... it has no intrinsic anti-hiv activity (EC50 > 30μmol/L) Cobi has similar inhibition to ritonavir on CYP3A4 Cobicistat acts on the CYP3A enzymes via a similar mechanism but with a slightly lower effectiveness than ritonavir: (kinact/ki of 0.57 vs min 1 µm 1respectively) Mathias AA et al., American Society for Clinical Pharmacology and Therapeutics, Vol 87:3 ; March 2010

6 Xu et al, ACS Med. Chem. Lett. 2010, COBI

7 The experimental pharmacoenhancer cobicistat (COBI), a potent mechanism-based inhibitor of cytochrome P450 3A enzymes, was found to inhibit the intestinal efflux transporters P-glycoprotein and breast cancer resistance protein. Consistent with its transporter inhibition, COBI significantly increased the absorptive flux of potential candidates for clinical coadministration, including the HIV protease inhibitors atazanavir and darunavir and the lymphoid cell- and tissue-targeted prodrug of the nucleotide analog tenofovir, GS-7340 (TAF).

8 Drug interactions of COBI as a CYP3A4 inhibitor

9 Transporter Pharmacology: Hepatic Transporter for: - Bilirubin - Several Statins - Cyclosporine - Some HCV DAAs Rosuvastatin AUC Rosuvastatin Cmax DRV/r (bd) 48% 144% DRV/cobi No data* No data* EVG/cobi 38% 89% * Plasma concentration of Rosuvastatin expected to increase Li R et al Clin Pharmacokinetic 2014; 53:

10 Comparison of Induction Potential of COBI and RTV: Activation of PXR Cobicistat is not expected to induce CYP3A4 or other enzymes/transporters. Ritonavir induces UGT1A1; CYP1A2, CYP2C8, CYP2C9, CYP2C19 Tyboost spc

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12 Different interaction with various medication Drugs with other than CYP3A4-mediated metabolism *Rezolsta SmPC 2015

13 CYP3A4 Results: From a total of 84 genes analysed, both COBI (1.28 µm) and RTV (1 µm) induced the expression (by 2-fold above control) of three genes each CYP3A4 expression induced by COBI or RTV relative to that of RIF-induced expression, was 49.0 ± 10.8%, or 56.7 ± 7.2%, respectively. COBI 1,28 µm RIF 10 µm RTV 1 µm CYP2B6 The expression of CYP2B6 by COBI and RTV relative to that of RIF was 37.5 ± 10.4%, and 57.9 ± 12.0%, respectively, whilst the corresponding induction of CYP2C8 expression by COBI and RTV compared to that of RIF was 54.9 ± 11.2%, and 53.7 ± 14.8%. Conclusions: COBI 1,28 µm RIF 10 µm RTV 1 µm CYP2C8 This model can provide a valuable description of the mechanisms underpinning DDIs and these results represent useful data to inform future clinical investigations of potential DDIs in HIV patients. Future developments: COBI and RTV: the same impact in vivo? What role in polypharmacy? University of Liverpool Clinical Pharmacology Department COBI 1,28 µm RIF 10 µm RTV 1 µm Owain Roberts, Chiara Carcieri, Catia Marzolini, David Back, Andrew Owen, Marco Siccardi.

14 An unexpected interaction between warfarin and cobicistat-boosted elvitegravir (BL Good et al, AIDS 2015 Increase of warfarin dose after switch from TDF/FTC/EFV to ELV/COBI/FTC/TDF Attributed to ELV inducing effect on CYP2C9 (main metabolizer of warfarin)

15 Different interaction with various medication Drugs with metabolism partly (and not primarily) mediated by CYP3A4 *Rezolsta SmPC 2015

16 Oestrogen based Contraceptives Ethinyloestradiol metabolised by CYP2C9, CYP3A4, & UGTs DRV/cobi or ATV/cobi May potentially increase exposure of EE DRV/r and ATV/r (to a lesser extent) decrease exposure of EE Data with DRV/r bd shows decrease in AUC of 44% - controindicated AND a OC with 30 mcg of EE is required for coadministration with ATV/r

17 Limits of ritonavir as a booster PK Issues.1 - Not selective as CYP3A4 inhibitor - CYP2D6 inhibitor - CYP2C9, CYP2C19, CYP1A2, UGT inducer - Inhibitor of membrane transporters COBI more selective, but clinical data needed (induction?)

18 Limits of ritonavir as a booster PK Issues.1 - Not selective as CYP3A4 inhibitor - CYP2D6 inhibitor - CYP2C9, CYP2C19, CYP1A2, UGT inducer - Inhibitor of membrane transporters COBI more selective, but cliinical data needed (induction) PK issues. 2 - Duration/persistence of boosting effect

19 COBI vs RTV: some basic pharmacologic features COBI RTV Molecular weight T/2 3.5 hours 3.5 hours Protein binding 97-98% 98-99% Renal clearance < 10% 3.5% Volume of distribution 77 L L

20 Concentration-effect relationship of CYP3A4 inhibition by RTV RTV booster dose (100 mg) was chosen for convenience (lower formulation available) Some evidence of similar boosting effect at lower dosage (e.g. 50 mg) (Eichbaum, Eur J Clin Pharm 2013) (Estevex, JAC 2012)

21 Concentration-effect relationship of CYP3A4 inhibition by COBI COBI underwent to a real dose-finding study as a booster agent 100 mg 200 mg Mathias, Nature, 2010

22 Comparative effects of cobicistat and RTV on Elvitegravir in vivo Mean EVG PK (n=42) EVG/COBI 100mg EVG /COBI 150mg EVG/RTV 100mg AUC tau (ng.hr/ml) C max (ng/ml) C tau (ng/ml) % Mathias A et al, GS-9350: A Pharmacoenhancer Without anti-hiv Activity Clincial pharmacology and therapeutics,87:3

23 RTV overdosed in the clinical setting? Susceptibility of boosting effect at decrease of booster plasma exposure is higher with COBI than with RTV? Do we have to pay more attention to DDIs affecting COBI exposure than we did with RTV?

24 Different interaction with various medication Pending data on effect on COBI exposure and activity by concomitant CYP3A4 inducers (e.g. etravirine) *Rezolsta SmPC 2015

25 ATV/COBI Bioequivalent to ATV + RTV Pharmacokinetics 42 healthy volunteers randomized to ATV + cobicistat 150 mg or RTV 100 mg once daily for 10 days 2 4-day washout period between regimens Doses were taken with a 400-kcal meal ATV + c ATV + r Ramanathan et al. ICAAC 2009, Abstract A

26 COBI equivalent to RTV as a DRV booster Ramanthan IWCPH 2013 Kakuda, IWCPH 2012

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28 Limits of ritonavir as a booster PK Issues.1 - Not selective as CYP3A4 inhibitor - CYP2D6 inhibitor - CYP2C9, CYP2C19, CYP1A2, UGT inducer - Inhibitor of membrane transporters PK issues. 2 - Duration/persistence of boosting effect COBI more selective, but cliinical data needed (induction) COBI = RTV, but clinical data needed (COBI Pk vs DDIs)

29 Limits of ritonavir as a booster PK Issues.1 - Not selective as CYP3A4 inhibitor - CYP2D6 inhibitor - CYP2C9, CYP2C19, CYP1A2, UGT inducer - Inhibitor of membrane transporters PK issues. 2 - Duration/persistence of boosting effect COBI more selective, but cliinical data needed (induction) COBI = RTV, but clinical data needed (COBI PK vs DDIs) Toxicity

30 Phase 3 GS-114: COBI vs. RTV with ATV+FTC/TDF Study Design Randomized, double-blind, double dummy, international study Treatment-naïve HIV RNA 5000 c/ml Any CD4 cell count egfr >70 ml/min (N=692) Stratification by HIV RNA (> or 100,000 c/ml) n=344 n=348 ATV + COBI + FTC/TDF Placebo: RTV ATV + RTV + FTC/TDF Placebo: COBI 48 weeks 192 weeks Primary Endpoint Primary Endpoint: Non-inferiority (12% margin) of COBI to RTV with ATV+FTC/TDF by FDA snapshot analysis HIV-1 RNA <50 copies/ml at 48 weeks egfr: estimated glomerular filtration rate by Cockcroft Gault Gallant J, et al. IAC 2012; Washington, DC. Oral TUAB0103

31 Study 114 Adverse Events (AEs) ATV + COBI (n=344) ATV + RTV (n=348) Bilirubin-related AEs * 41% 36% Nausea 18% 16% Diarrhea 15% 20% Headache 11% 16% Nasopharyngitis 11% 15% Upper respiratory infection AEs occurring in 10% 10% 8% * Bilirubin-related AEs include jaundice, ocular icterus, hyperbilirubinemia, and blood bilirubin increased. AEs* Discontinuations due to AEs Study drug discontinued due to any AE, (n) ATV + COBI (n=344) ATV + RTV (n=348) 7.3% (25) 7.2% (25) Bilirubin-related AEs 3.5% (12) 3.2% (11) Renal abnormalities** 1.7% (6) 1.4% (5) Rash 0.3% (1) 0.6% (2) Dermatitis allergic 0.6% (2) 0 >1 subject in either group ** Proximal tubulopathy: serum Cr increase along with 1 of the following abnormalities - hypophosphatemia, proteinuria, normoglycemic glycosuria 5/6 in ATV+COBI versus 2/5 in ATV+RTV discontinued due to proximal tubulopathy** Gallant J, et al. IAC 2012; Washington, DC. TUAB

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33 COBI Xu et al, ACS Med. Chem. Lett. 2010,

34 Limits of ritonavir as a booster PK Issues.1 - Not selective as CYP3A4 inhibitor - CYP2D6 inhibitor - CYP2C9, CYP2C19, CYP1A2, UGT inducer - Inhibitor of membrane transporters PK issues. 2 - Duration/persistence of boosting effect COBI more selective, but cliinical data needed (induction) COBI = RTV, but clinical data needed (COBI PK vs DDIs) Toxicity COBI = RTV, but clinical data needed (lipids, insulin, )

35 Conclusions There are few but important differences between RTV and COBI COBI can be much easier coformulated Less DDIs due to selective CYP3A4 activity (lack of induction to confirm in the clinical setting) Similar PK robustness to confirm in the clinical setting No significant difference of tolerability in a single clinical trial but more clinical data are needed (promising differences in vitro)

36 PK lab Antonio D Avolio Jessica Cusato ID Unit Andrea Calcagno Letizia Marinaro Laura Trentini Cristina Tettoni Chiara Alcantarini Stefani Raviolo Micol Ferrara Maurizio Milesi Chiara Montrucchio Ambra Barco Prof Giovanni Di Perri Marco Simiele Lorena Baietto Alessandra Arialdo Amedeo De Nicolò Sarah Allegra Debora Pensi Mauro Sciandra Viro lab Tiziano Allice Maria Grazia Milia Valeria Ghisetti